It was approved by the American Food and Drug Administration in 2010 for use in children aged two years and above.1,3

IV paracetamol is prominently indicated for post-operative analgesia and has shown efficacy in reducing postoperative nausea and vomiting when used prophylactically.

Indications for the use of IV paracetamol

The indications for the use of IV paracetamol include:

  • Treatment of mild to moderate pain and fever when alternate routes of administration are not possible and/or there is an urgent need for therapy
  • Treatment of moderate to severe pain as part of a multimodal approach to analgesia (given its’ opioid-sparing properties either as an alternative or supplement)
  • When opioids are either contraindicated or there are considerable concerns surrounding the adverse effects of opioids.1-4

IV paracetamol is prominently indicated for post-operative analgesia and has shown efficacy in reducing postoperative nausea and vomiting when used prophylactically. Several studies have demonstrated the adequacy of analgesia while demonstrating less sedation and shorter recovery times.3

Despite the proven efficacy of paracetamol as an analgesic the exact mechanism of action remains incompletely understood. It acts at both central and peripheral components of the pain pathway.2,3

In addition to inhibition of cyclo-oxygenase enzymes (reduction of prostaglandin production via inhibition of prostaglandin synthase), paracetamol acts on the endogenous opioid, serotoninergic bulbospinal and nitric oxide pathways.2,3

Lastly, paracetamol also appears to act on both N-methyl-D-aspartate (NMDA) and cannabinoid CB1 receptors in the brain and spinal cord.2,3

Rapid onset of action

IV paracetamol has a rapid onset of action with analgesic and antipyretic effects within 15 and 30 minutes, respectively.2,3

The speed of onset of analgesia is due to a rapid time to maximum plasma concentration of 15 minutes as compared to 45 minutes (oral) and three to four hours (rectal).3

IV paracetamol rapidly crosses the blood-brain barrier achieving higher cerebrospinal fluid (CSF) concentrations and more effective antipyretic effects for the first 60 minutes compared to an equivalent oral dose. Peak analgesic effects are achieved by 1 hour and both analgesic and antipyretic effects last up to 6 hours.2,3

Safety profile of IV paracetamol

The safety profile of IV paracetamol is favourable compared to either non-steroidal anti-inflammatory drugs (NSAIDs) or opioids.2 Adverse effects include nausea and vomiting, constipation, pruritis, agitation and atelectasis.3

Significant adverse reactions are extremely rare (<1/10000) and include the development of asthma, rhinoconjunctivitis and eczema in adolescents.1,2

NB: It is very important to check the dosing regimen of IV paracetamol as it is not the same as the dosing regimen for oral paracetamol and problems have arisen from either the incorrect use of doses recommended for the oral drug and/or dosing errors where milligrams(mg) are replaced by milliliters (ml).5

Dosing of IV paracetamol

The dosing of IV paracetamol in children depends on both age and weight. Infusions of IV paracetamol are given over 15 minutes with a minimum interval of four hours between doses. Table 1 is largely based on the dosing recommendations of the Medicines and Healthcare products Regulatory Agency (MHRA) of the United Kingdom(UK).1,3

Table 1: Paediatric dosing of IV paracetamol

The MHRA dosing regimen for infants, term and preterm neonates has recently been challenged due to concerns of underdosing. The details of the two proposed regimens (based on gestational age) are as follows:

  1. A six-hourly dosing interval of 10mg/kg (28-<32 weeks) or 12.5mg/kg (32-<36 weeks) or 15mg/kg (≥36 weeks) 6
  2. A loading dose of 20mg/kg followed by 10mg/kg for preterm neonates or 15mg/kg for term neonates and older infants. The dosing interval should be six hourly for neonates/infants born after 31 weeks gestation or 12 hourly for those born between 28 and 31 weeks gestation.5

 

Pharmacokinetics

IV paracetamol is metabolised by the liver predominantly via glucuronidation and sulfation. At higher doses, additional metabolism via the cytochrome p450 pathway produces N-acetyl-p-benzoquinone (NAPQI) which rapidly conjugates with glutathione and is excreted in the urine.1,2

The majority (90%) of the metabolised drug is excreted in urine within 24 hours with <5% of the drug excreted unchanged. With toxic doses, the excess of NAPQI produced depletes available glutathione resulting in hepatocellular damage by unconjugated NAPQI.1,2

While IV paracetamol remains contra-indicated in patients with severe and active liver disease, it is safe to use at recommended doses in patients with mild to moderate liver dysfunction.1,2

There is a greater risk of toxicity in patients predisposed to lower levels of glutathione (chronic malnutrition, severe dehydration) even within recommended dosing limits.1,3

Caution should also be exercised in neonates with unconjugated hyperbilirubinaemia.6

Drug clearance is slower in children younger than two years of age so six-hourly dosing intervals is preferable. Furthermore, as a result of delayed clearance due to severe renal dysfunction (creatinine clearance <30ml/min), the minimum dosing interval should be increased from four to six hours.2

With respect to infusion, IV paracetamol is physically incompatible with both diazepam and chlorpromazine hydrochloride.3

Lastly, studies in adults have raised concerns of decreased blood pressure upon administration of IV paracetamol. This has recently been investigated among paediatric patients.

A retrospective chart review of 100 patients found no haemodynamically significant impact following the administration of IV paracetamol. Decreases in blood pressure were usually from supra-normal levels to normal levels, due to the relief of pain.7

However, a second study among 45 children with septic shock found a decline in mean arterial pressure of at least 15% following 32.4% of doses which necessitated the administration of either a fluid bolus or increase in inotropic dose after 11.4% of doses.8

The difference in the findings of the two studies are attributable to the different patient populations (only three patients with septic shock in the first study) and the indications for the paracetamol (68% pain in the first study and 79% fever in the septic shock study).

Thus, among haemodynamically unstable children, the administration of IV paracetamol may result in clinically significant hypotension and should be used with caution.

REFERENCES:

  1. Irshad MI, Malik M, Furqan A. Intravenous paracetamol in pediatrics: A global perspective. Anaesth Pain & Intensive Care. 2012;16(3);311-4.
  2. Duggan ST, Scott LJ. Intravenous Paracetamol (Acetaminophen). Drugs. 2009;69(1):101-13
    Shastri N. Intravenous acetaminophen use in pediatrics. Pediatr Emerg Care. 2015;31:444-8.
  3. Zhu A, Benzon HA, Anderson TA. Evidence for the efficacy of systemic opioid-sparing analgesic in pediatric surgical populations: a systemic review. Anesth Analg. 2017;125:1569-87
  4. Veyckermans F, Anderson BJ, Wolf AR, Allegaert K. Intravenous paracetamol dosage in the neonate and small infant. Br J Anaesth. 2014;112(2):380-94
  5. Palmer GM, Atkins M, Anderson BJ, Smith KR, et al. IV acetaminophen pharmacokinetics in neonates after multiple doses. Br J Anaesth. 2008;101(4):523-30
  6. Nahum E, Friedman M, Kaplan E, Weissbach A, et al. The Hemodynamic Effect of Intravenous Paracetamol in Children: A Retrospective Chart Review. Pediatric Drugs. 2019;21:177-83
  7. Nahum E, Weissbach A, Kaplan E, Kadmon G. Hemodynamic effects of intravenous paracetamol in critically ill children with septic shock on inotropic support. Journal of Intensive Care. 2020;8:14

 

Specialist Forum January 2022 CPD